Sequence Of Amino Acids In A Polypeptide Biology Essay


The final 3 D structure of a protein is, to a great degree, determined by the type of amino acids that make the sequence. Since each different amino acid has different structures, it results in the formation of poly peptide chain with various conformations (spatial arrangement of atoms in space). Basically there are about four levels of protein structure arranged on the basis of conceptual hierarchy.

Secondary structure: It represents the regular folding pattern of the polypeptide backbone, usually the primary structures held together by the hydrogen bond or the disulphide bond result in the formation of secondary structure. There are two type of secondary structure i.e. α-Helix and β-sheet.

Tertiary structure: It represents all the 3-D folding of a polypeptide chains. Unlike the secondary structure where the hydrogen bonding stabilize the structure, the tertiary structure involves a long range aspect of amino acid sequence and the hydrophobic interaction plays a key role in stabilizing its structure.

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(Source:- Lodish et al, 2004)

Tertiary structure is also held together by formation of disulfide bonds (disulfide bridge). Disulfide bonds are formed by oxidation of two thiol groups (SH) between the side chains of cysteine to form a disulfide bond (S-S).

(Source: Wilson & Walker, 2005)

Quaternary structure: it represents two or more separate polypeptide chains or subunits joined together by a non covalent bond.

(Source: Weil, 2008)

Fig. Four levels of protein structure

(Source: Kratz, 2009)

How the sequence of amino acids affects the final 3-D structure of proteins

To fully understand how the sequence of amino acids influences the final 3D structure of protein, it is important to first understand how the formation of secondary structure is influenced by it. It is obvious that different amino acid involved in the formation of primary structure form a definite secondary structure based on the R-group attached to it.

Amino acids affect the stability of α-helix.

α-helix is the polypeptide backbone wound around the imaginary axis with the R-group of the amino acid protruding outward. α-helix has 3.6 amino acids per turn of the helix.

Fig. Structure of α-helix

(Source: α-helix, n.d)

Since each amino acid differs in their structure and chemical properties, their presence in the polypeptide chain affect the stability of α-helix. There are five factors that determine the stability of α-helix;

(Source: Lehninger, 1978)

The electrostatic repulsion or attraction between the successive amino acids with a charged R-group.

The tertiary structure of the polypeptide chains depends on the interaction of the R-groups present in various amino acids; therefore it represents the non repetitive aspects of the poly peptide chain. The tertiary structure is not at all predictable as it depends entirely on the side chains with different chemical properties. For example the hydrophobic R group will always occupy the interior side of the molecule away from the exterior aqueous environment, whereas the polar R-group will occupy the outer side of the molecule due to the attraction from the polar water molecules in the surrounding media.

The bulkiness of the adjacent R-group

The α-helix is also destabilized, if Asn, Ser, Thr and Leu are present close to each other in the polypeptide chain. This is due to their bulky structure and shape.

(Source: Wilson & Walker, 2005)

The interactions between amino acid side chains

Due to these interactions between the side chains of various amino acids, the α-helix is either stabilized or destabilized. For example, a poly peptide chain with a long sequence of glutamine will not form the alpha helix at pH 7.0. This is because the negatively charged carboxylic group of glutamine will repel each other to such an extent that it will overcome the stabilizing effect of the hydrogen bonds. Similarly the polypeptide chain with a long sequence of lysine or arginine will also prevent the formation of alpha helix at neutral pH, as they have a positively charged R-group, which repel the overcoming force of hydrogen bond.

(Source: Freifelder et al, 1998)

Fig. Amino acid with negatively charged R-group

(Source: Negatively charged R-Group in Polypeptide Chain. n.d.).

The occurrence of proline or glycine

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The presence of proline in the sequence destabilizes the alpha helix. The nitrogen atom of the proline is the part of the rigid ring, therefore rotation about the N-Cα ­ is not possible and the nitrogen atom of proline in the peptide linkage does not have hydrogen atom which can take part in hydrogen bond formation. Therefore, proline is rarely found in α-helices. On the other hand, the glycine is not commonly found in the α-helix due to different reason.

The interaction between the amino acid at the end of the helical segment and the electric dipole inherent to the alpha helix

Since a partial positive charge resides on the amide nitrogen of the N terminus and a partial negative charge resides on the carbonyl oxygen, therefore an electric dipole exists in the peptide bond. When they are connected by the hydrogen bond (though four amino acids at the end of the helix does not take part in the formation of hydrogen bond), a net dipole extends through the axis of α-helix.

Fig. Alpha helix with a net dipole on it

(Source: Charge on the α-helix. n.d.)

The interaction between the amino acid and the electric dipole at the end of the helical segment also determines the stability of the α-helix.

The negatively charged amino acids have a stabilizing interaction with the positive charge and hence they are often found near the amino terminal. In the similar way, the positively charged amino acid will often be found towards the carbonyl terminal as there will be a stabilizing interaction with the negative charge present on it. But if the negatively charged amino acids are present on the carbonyl terminal and the positively charged amino acids are present on the amino terminal, then it will lead to the destabilizing of the alpha helix.

(Wilson & Walker, 2005)

How the amino acids affects the β-sheet structure

In β-sheets, the poly peptide backbone is extended into the zig zag structure. The hydrogen bonds are formed between the adjacent polypeptide chains with the R-group protruding from the zig zag surface in the opposite direction. The structure of amino acids also plays a very vital role in the formation of beta sheets layer in the protein. Importantly, the R-group (of the amino acids in the β-sheets) touching the surface should be small when they are stacked over one another.

Fig. Structure of β-sheet

(Source: β-sheet, n.d)

Amino acids affects the formation of β-turns

β-turns are 1800 turn structure which connects the alpha helix to α-helix and the β-sheets. It involves four amino acids where a hydrogen bond is formed between the carbonyl oxygen of first amino acids and the amino group hydrogen of the fourth amino acids. Glycins and proline are often found in the β- turn because the glycine is small and flexible where as the nitrogen of proline readily acquires the cis configuration. Most of the other amino acids are unable to form β- turn as readily as the glycine and proline. Therefore they are unable to connect the alpha helix and beta sheets to form the tertiary structure.

(Source: Nelson et al, 2000)

Fig. structure of β-turns

(Source: β-turns, n.d)

ψ and φ angle

One of the factors that determine the final 3 D structure of the protein is that, certain secondary structures have a particular bond angle (ψ and φ) and amino acids. In the polypeptide chain, every third bond has some double bond character. This double bond character restricts the free rotation. And the side chain of some of the amino acids such as the isoleucine or lysine is not compatible with the formation of stable α- helix. Based on this observation, Ramachandran predicted φ and ψ values for the formation of α-Helix and β-sheets. The φ and ψ values of most of the proteins fall in the predicted region except for the Glycine. The glycine has a single hydrogen atom and can take part in many conformations, whereas most of the other amino acids are forbidden.

(Source: Lehninger, 1978)

Therefore, different ψ and φ angle are formed between the amino acids in the polypeptide sequence and this leads to the formation of tertiary structure with various stearic conformations, thus, affecting the 3-D structure of proteins.

The diversity of protein structure (how structure determines the functions for proteins)

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The final 3-D structure of the polypeptide chain is the tertiary level of protein structure. Based on this three dimensional structure of the proteins, there are two categories of protein;

Globular proteins:-

In this type, the polypeptide chains are folded into a spherical or globular shape. In fact every globular protein has its own unique tertiary structure formed out of secondary structure folded in a specific way to suit the particular function of the protein. This protein includes enzymes, transport proteins, motor proteins, regulatory proteins, immunoglobins, and other proteins.

(Source: Lodish et al, 2004)

Most globular protein contains a number of segments called domains. A domain is a distinct, locally folded unit of tertiary structure often consisting of regions of α-helices and β-sheets compactly packed together. Small globular proteins have a single domain whereas large globular proteins have multiple domains.

(Source: - Becker et al, 2006)


1. Myoglobin. It consists of single polypeptide chain of 153 amino acid residues. It has an iron-porphyrin or heme which is also present in case of hemoglobin. The α-helix is right handed and the longest one composes of 23 amino acids and the shortest one composes of only 7 amino acids. The polar R-group of the amino residues are hydrated and present on the outer side. The hydrophobic R-group are present towards the inner side away from the exterior aqueous environment. At the bends, molecules like proline, isoleucine and serine which do not form α-helix are found.

Source: Lihninger, (1995)

The oxygen carried by the myoglobin is usually bound directly to the ferrous ion (Fe2+) which gets oxidized to ferric ion (Fe3+ ) . This oxidation makes the myoglobin incapable of binding more oxygen. Therefore the hydrophobic interaction between the tetrapyrole ring and the hydrophobic R-group of the amino acids on the inner side of protein stabilizes the heme protein conjugate. The coordination between the iron and the nitrogen atom of the R-group of histidine located above the plane of heme ring further stabilizes the interaction between the heme and the protein.

In oxymyoglobin the remaining bonding site on the iron atom is occupied by the oxygen whose interaction is stabilized by a second histidine residue.

The structure of myoglobin with the presence of heme group enables the myoglobini molecule to bind oxygen and serve as an intracellular storage site of oxygen. During periods of oxygen deprivation, oxymyoglobin releases the bound oxygen which is used by the cell for metabolic purposes. (Source: Hemoglobin and Myoglobin, n.d)

Fig. the structure of myoglobin

(Source: Hemoglobin and Myoglobin, n.d)

Hemoglobin is a tetrameric heme protein found in the erythrocytes. It bind the oxygen in the lungs and transport it throughout the body for metabolic processes. The hemoglobin tetramer has four heme groups that is identical to the myoglobin. Due to the quaternary structure of hemoglobin, it exhibits allosteric properties.

Fig. structure of hemoglobin

(Source: Hemoglobin and Myoglobin, n.d)

When oxygen is bound to the first subunit of deoxyhemoglobin, the affinity of the remaining subunit for the oxygen increases. As additional oxygen is bound to the second snd third subunits, the oxygen binding capacity is further enhanced. Therefore in the alveoli of lungs, the hemoglobin is fully saturated. The oxyhemoglobin circulates through the tissues and delivers oxygen and the affinity of hemoglobin for oxygen is reduced. Therefore in the active tissues where the metabolic activity is very high, the affinity of the hemoglobin is very low allowing the maximum delivery of oxygen

The oxygen binding curve of hemoglobin is of sigmoidal type where as the oxygen binding curve of myoglobin is hyperbolic type indicating that myglobin do not exhibit allosteric interaction.

(Source: Hemoglobin and Myoglobin, n.d)

The different properties and functions exhibited by myoglobin and hemoglobin are all because of their structures. The presence of only one heme group in the myoglobin and the presence of four such heme groups in hemoglobin has resulted in different functions that are performed by them. And also the allosteric interaction of hemoglobin and the inability of the myoglobin to exhibit allosteric interaction show that structure of a particular protein is responsible for its functions.

2.Enzymes. Most of the enzymes are globular proteins. It includes ribonuclease, lysozyme and many more. Ribonuclease is a globular protein secreted by pancreas in the small intestine. It contains about 124 amino acids residues. Most of these amino acids are present in β-form than the β-form. This enzyme brings about the hydrolysis of certain bonds in the RNAs present in the ingested food. Four disulfide bonds are also present in the loops providing stability to the structure.

(Source: Lodish et al, 2004)

Lysozyme is commonly found in egg white and human tears. In tears it hydrolysis the polysaccharides in the protective cell walls of some bacteria. Of the 129 amino acids residues present in lysozyme, 40% of it occur in α-helical segment arranged differently. Sometimes β-sheet structure are also present. The molecule has active sites for substrate binding and catalysis. The molecule has four disulphide bond which contribute to the stability to the structure.

(Source: Nelson et al,2000)

Fig. structure of lysozyme

(Source: lysozyme, n.d.)

Fibrous proteins

Fibrous proteins are long and cable-like structural proteins which are adapted for structural functions. Cytoskeletal proteins are the fibrous protein important for the structure of the cell.

(Source: Kratz, 2009)

The secondary structure is much more important than the tertiary structure in case of fibrous protein because they have extensive secondary structure giving them a repetitive structure. Silk fibroin, collagen, elastin and the keratin of hair and wool are some of the fibrous protein. Generally all fibrous proteins are insoluble in water as it as hydrophobic residues in the interior as well as on the exterior side.

(Source: Becker et al, 2006)

Example : α-keratin. It is a fibrous protein that is found in the hair, wools, nails, claws, horns, hooves, feathers and on the outer surface of the skin. Francis Crick and Linus Pauling in early 1950s described the structure of α-keratin. They said that the two alpha helices oriented in parallel are twisted about one another to form a super twisted coil. The supertwisting of the α- helices provides the overall strength of the α-keratin. The twisting of the α-keratin is left handed and is just opposite to that of α-helix. The surfaces where the two α-helices touch each other are made up of hydrophobic amino acid residue and their R-group combine in the interlocking pattern. This enables the polypeptide chain to be closely packed within the supertwist. The two α-helices intertwine to form a quaternary structure which is much more complex. Such structures are found in the intermediate filament of hair. The presence of cross-linking (disulpide bond) between the polypeptide chains in the alpha keratin also provides strength to the structure.

(Source: Nelson et al, (2005).

Example to show that the primary structure (i.e sequence of amino acid) determines the tertiary structure of protein and how the tertiary structure determines the function.

In case of person suffering from sickle celled anemia, the RBCs are distorted from their normal disc shaped into the sickle shaped structure. Due to this they block the blood vessels impeding the blood flow. This condition has resulted from the slight change in the hemoglobin within RBCs. In the distorted RBCs, the haemoglobin has a normal α-chain, but the β-chain have one different amino acid. Usually the glutamate which is present at the specific position on the sixth residue from the N-terminus is replaced by the valine and the other 145 sequence are in their correct order. This single substitution changes the tertiary structure of β-sheet and the haemoglobin molecule tends to crystalize deforming the shape of RBCs into sickle shaped. The sickle shaped RBCs have low oxygen affinity and therefore it functions differently than the normal disc shaped RBCs.

This shows that the sequence of amino acids determines the tertiary structure of protein and the tertiary structure is responsible for determining the function of protein.